Method for synthesizing 3-chloro-bicyclo [1.1. 1] pentylamine salt and intermediate thereof

Abstract

The invention provides a method for synthesizing 3-chloro-bicyclo [1.1. 1] pentylamine salt and an intermediate thereof, and belongs to the technical field of medicine synthesis. According to the method, bicyclo [1.1. 1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester is adopted as an initial raw material, the 3-chlorine bicyclo [1.1. 1] pentylamine salt is obtained under mild and appropriate conditions through the steps of visible light catalytic decarboxylation chlorination, hydrolysis, rearrangement and deprotection, the whole route is simple to operate, the used raw materials are commercially available and easy to obtain, the total yield of a hectogram-grade product is up to 41.27%, the product purity is up to 98.3%, and the method is suitable for industrial production. Through amplification and parallel batch verification, hectogram-level products can be stably obtained, and the method is safe and suitable for amplified production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt and an intermediate thereof. Background Art

[0002] In recent years, bicyclo[1.1.1]pentane (BCP) compounds with three-dimensional structures have attracted much attention in the field of pharmaceutical synthesis. They not only exhibit unique physiological activities, but are also bioisosteres of benzene rings, internal alkynes, and tert-butyl groups. They are widely used in drug design and are favored by pharmaceutical chemists. 3-Chlorobicyclo[1.1.1]pentylamine hydrochloride, as an important member of bicyclo[1.1.1]pentane compounds, is an important intermediate in pharmaceutical synthesis and can be used as a molecular building block in the synthesis of a variety of drugs. For example, patent application WO2022241023A1 reports an LPA receptor antagonist compound A that may be used to treat liver disease:

[0003]

[0004] Patent application WO2016044331A1 discloses a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine hydrochloride, the route is as follows:

[0005]

[0006] However, the total yield of the four steps of this method is only 7.56%, which is not suitable for large-scale production. Summary of the invention

[0007] The object of the present invention is to provide a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt and its intermediates.

[0008] The present invention provides a method for synthesizing a 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II, which comprises the following steps: mixing a compound I, trichloroisocyanuric acid, a metal catalyst and a base in a solvent, reacting under visible light illumination to obtain a 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II;

[0009]

[0010] Further, the metal catalyst is selected from a cerium catalyst and an iron catalyst;

[0011] The base is selected from an organic base or an inorganic base;

[0012] The solvent is selected from an organic solvent, water or a mixture of the two;

[0013] The wavelength of the visible light is 400nm to 500nm;

[0014] The reaction time is 6 to 20 hours, the temperature is 5 to 35° C., and the reaction is carried out in an air atmosphere;

[0015] The molar ratio of the compound I, trichloroisocyanuric acid, metal catalyst and base is 1: (0.3-0.7): (0.05-0.3): (0.1-0.5);

[0016] The mass volume ratio of the compound I to the solvent is 1: (40-80) g / mL.

[0017] Furthermore, the cerium catalyst is selected from CeCl 3 , CeBr 3 、Ce(SO 4 ) 2 ; The iron catalyst is FeBr 2 ;

[0018] The organic base is sodium alkoxide, preferably sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, sodium n-butoxide or sodium isobutoxide;

[0019] The inorganic base is potassium carbonate or sodium carbonate;

[0020] The solvent is selected from an organic solvent and a mixture of an organic solvent and water, and the organic solvent is selected from acetonitrile and dichloromethane; in the mixture of the organic solvent and water, the volume ratio of the organic solvent to water is preferably 1:(0.5-2), more preferably 1:1;

[0021] The wavelength of the visible light is 440nm;

[0022] The reaction time is 8 to 14 hours, and the temperature is 10 to 30°C;

[0023] The molar ratio of the compound I, trichloroisocyanuric acid, metal catalyst and base is 1:0.5:0.1:0.3;

[0024] The mass volume ratio of the compound I to the solvent is 1:59 g / mL.

[0025] Furthermore, in the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II, after the reaction is completed, the following purification step is also included: the reaction solution is concentrated and then diluted with petroleum ether, the pH is adjusted to pH=3, and the liquids are separated; the aqueous phase is extracted with petroleum ether again; the liquids are separated; the organic phases after the two separations are combined, washed with 2M hydrochloric acid, the organic phase is dried, and concentrated.

[0026] The present invention also provides a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, the method comprising the following steps:

[0027] (1) Synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II according to the above method;

[0028] (2) hydrolyzing the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II to obtain the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III;

[0029]

[0030] Furthermore, in step (2), the hydrolysis is carried out under acidic conditions.

[0031] Furthermore, in step (2), the hydrolysis is carried out in the presence of concentrated sulfuric acid, the mass volume ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II to concentrated sulfuric acid is 1:(2-4), preferably 1:3; the hydrolysis temperature is 40-60°C, preferably 50°C; the hydrolysis is carried out in a mixture of tetrahydrofuran and water; the hydrolysis is carried out under the protection of an inert gas.

[0032] Furthermore, in the mixture of tetrahydrofuran and water, the volume ratio of tetrahydrofuran to water is 1:(0.5-2), preferably 1:1.

[0033] Furthermore, after the reaction in step (2) is completed, the following purification step is also included: the reaction solution is concentrated and then water is added, extracted with dichloromethane, the organic phase is collected, dried and concentrated, and purified by column chromatography.

[0034] The present invention also provides a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate IV, the method comprising the following steps:

[0035] (a) synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III according to the above method;

[0036] (b) reacting 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide and a base in a solvent containing tert-butyl alcohol to obtain compound IV;

[0037]

[0038] Furthermore, in step (b), the base is an inorganic base or an organic base, and the organic base is preferably triethylamine or N,N-diisopropylethylamine; the solvent is tert-butyl alcohol or a mixture of tert-butyl alcohol and toluene; step (b) comprises the following operations: (b1) 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide, base and solvent are mixed and reacted, concentrated, dissolved in dichloromethane, washed with water, and dried; (b2) solvent is added to dissolve, reacted to obtain compound IV.

[0039] Furthermore, in step (b1), the molar ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide and the base is 1:(1.05-1.5):(2-4), preferably 1:1.1:3; the mass volume ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III to the solvent in step (b1) is 1:(5-30) g / mL, preferably 1:(10-20) g / mL; the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III is 1:(5-30) g / mL, preferably 1:(10-20) g / mL. The mass volume ratio of intermediate III to the solvent in step (b2) is 1: (5-30) g / mL, preferably 1: (10-20) g / mL; the reaction temperature in step (b1) is 25±10°C, preferably 25±5°C, and the reaction time is 1-3 hours, preferably 2 hours; the reaction temperature in step (b2) is 80-110°C, preferably 90°C, and the reaction time is 6-20 hours, preferably 8-14 hours; the reaction is carried out under the protection of an inert gas.

[0040] Furthermore, after the reaction of step (b) is completed, the following purification step is also included: filtering the reaction solution, concentrating it, adding water, extracting it with ether, collecting the organic phase, washing it with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, concentrating it, and purifying it by column chromatography.

[0041] The present invention also provides a method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt, the method comprising the following steps:

[0042] (i) synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate IV according to the above method;

[0043] (ii) Compound IV reacts with an acid to obtain 3-chlorobicyclo[1.1.1]pentylamine salt, i.e., Compound A;

[0044]

[0045] Wherein, X is an acid.

[0046] Furthermore, in step (ii), the acid is HCl.

[0047] Furthermore, in step (ii), the reaction solvent is an organic solvent, preferably 1,4-dioxane; the molar ratio of compound IV to acid is 1:(5-9), preferably 1:7; and the reaction condition is room temperature overnight.

[0048] The present invention has achieved the following beneficial effects:

[0049] In the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II of the present invention, visible light is used to decarboxylate and chlorinate bicyclo[1.1.1]pentane-1-carboxylic acid compounds. There is no report on the use of visible light to decarboxylate and chlorinate bicyclo[1.1.1]pentane-1-carboxylic acid compounds. In the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II reported in patent application WO2016044331A1, ultraviolet light is used for illumination, and two steps are required. Although the feed is continuously fed, it needs to be concentrated into the intermediate acyl chloride first, and the acyl chloride is not very stable and is easily deteriorated in humid air, and the yield of this step is very low.

[0050] In the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III of the present invention, hydrolysis is carried out under acidic conditions with a yield of up to 84.72%. In the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II reported in patent application WO2016044331A1, in the presence of LiOH.H 2 O conditions, the yield was less than 30%.

[0051] In the method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate IV of the present invention, by controlling specific reaction conditions, the yield is as high as 81.78%, which is much higher than the yield of this step in the method reported in patent application WO2016044331A1 (only 42%).

[0052] The invention provides a scalable process for preparing 3-chlorobicyclo[1.1.1]pentylamine salt and an intermediate thereof. Bicyclo[1.1.1]pentane-1-carboxylic acid-3-carboxylic acid methyl ester is used as an initial raw material, and a target product 3-chlorobicyclo[1.1.1]pentylamine salt is obtained under mild and suitable conditions through visible light catalytic decarboxylation chlorination, hydrolysis, rearrangement and deprotection steps. The whole route is simple to operate, and the raw materials used are all commercially available and easily available. The total yield of 100-gram-level products is as high as 41.27%, and the product purity is as high as 98.3%. After amplification and parallel batch verification, 100-gram-level products can be stably obtained, and the product is safe and suitable for scale-up production.

[0053] The route for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt and its intermediates proposed by the present invention has strong stability, adopts a new light decarboxylation chlorination technology, and has strong stability after amplification and multi-batch verification. Compared with the prior art, the first step of illumination adopts visible light, and the synthesis of intermediate II can be completed in one step, with higher yield and more environmental protection. The raw materials and reagents used in each step of the reaction are all commercially available, with less pollution to the environment and low material cost, which can reduce the production cost of the target product and promote its application in the medical field; under the reaction conditions of Example 1, the four-step total yield of this synthetic route at 100 grams is 41.27%, and the product purity is as high as more than 98%; under the reaction conditions of Example 1, the present application has been verified by 100 grams of preparation (Example 12), which is more suitable for industrial production than the prior art.

[0054] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0055] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the compound V obtained in Example 1 1 H-NMR spectrum.

[0057] Figure 2 This is the ELSD spectrum of compound V obtained in Example 1.

[0058] Figure 3 is the compound V obtained in Example 12 1 H-NMR spectrum;

[0059] Figure 4 is the ELSD spectrum of compound V obtained in Example 12; DETAILED DESCRIPTION

[0060] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0061] Overnight reaction means reaction for 8-14 hours.

[0062] Unless otherwise specified, the operations in the embodiments of the present invention are carried out at room temperature, which refers to 25±5°C.

[0063] Unless otherwise specified, the operations of the embodiments of the present invention are performed in an air atmosphere.

[0064] The route for synthesizing 3-chlorobicyclo[1.1.1]pentylamine hydrochloride (i.e., compound V) in the embodiment of the present invention is as follows:

[0065]

[0066] Embodiment 1:

[0067] Step 1: Preparation of Compound II

[0068] In an air atmosphere, compound Ⅰ (34 g, 199.807 mmol, 1 equiv), acetonitrile (1000 mL), water (1000 mL), trichloroisocyanuric acid (23.22 g, 99.9 mmol, 0.5 equiv), sodium tert-butoxide (5.76 g, 59.94 mmol, 0.3 equiv), and cerium chloride (4.92 g, 19.98 mmol, 0.1 equiv) were added to a 2 L jacketed reaction bottle; the temperature was controlled at 25 ° C, and the reaction was allowed to react overnight under 440 nm light, and the reaction was monitored by gas chromatography-mass spectrometry (GCMS) to be complete. After concentration, the reaction solution was diluted with petroleum ether (1000 mL), adjusted to pH = 3 with 6M hydrochloric acid, separated, and the aqueous phase was extracted with petroleum ether (3×200 mL). The organic phases were combined and washed once with 2M hydrochloric acid (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 22.2 g of yellow solid compound II with a purity of 97.18% and a yield of 67.23%.

[0069] Step 2: Preparation of Compound III

[0070] Under nitrogen protection, compound II (17.3 g, 107.721 mmol, 1 equiv), THF (277 mL), and H 2 O (277 mL), heat to 50 ° C, slowly add concentrated sulfuric acid (54 mL) dropwise; control the temperature at 50 ° C to react overnight; monitor by GCMS, concentrate, cool to room temperature, concentrate most of the organic solvent, add water (200 mL), extract with dichloromethane (3×500 mL), collect the organic phase, dry and concentrate, and purify by column chromatography (chromatography column packing: 200-300 mesh silica gel; eluent: ethyl acetate: petroleum ether = 5%-20%) to obtain 13.6 g of white solid compound III with a purity of 98.35% and a yield of 84.72%.

[0071] Step 3: Preparation of Compound IV

[0072] Under nitrogen protection, compound III (6.7 g, 45.712 mmol, 1 equiv), tert-butyl alcohol (67 mL), TEA (13.88 g, 137.136 mmol, 3 equiv) were added to a 1L three-necked flask, and DPPA (diphenylphosphoryl azide, 13.84 g, 50.283 mmol, 1.1 equiv) was slowly added dropwise at room temperature; stirred at room temperature for 2 h, concentrated, 100 mL of dichloromethane was added to dissolve, washed with saturated sodium chloride (3×50 mL), dried over anhydrous sodium sulfate, concentrated to dryness, tert-butyl alcohol (67 mL) was added to dissolve, and then the temperature was raised to 90°C and refluxed overnight, and the reaction was monitored by liquid chromatography-mass spectrometry (LCMS). Filter, concentrate, add water (300 mL), extract with ether (2×400 mL), collect the organic phase, wash with saturated sodium chloride solution (500 mL), dry over anhydrous sodium sulfate and concentrate, purify by column chromatography (chromatography column packing: 200-300 mesh silica gel; eluent: ethyl acetate: petroleum ether = 3%-10%) to obtain 8.138 g of white solid compound IV with a purity of >99% and a yield of 81.78%.

[0073] Step 4: Preparation of Compound V

[0074] Compound IV (8.138 g, 37.383 mmol, 1 equiv) was dissolved in 1,4-dioxane (41 mL). Under an ice bath, a 4M 1,4-dioxane solution of hydrogen chloride (66 mL, 7 equiv) was slowly added dropwise and stirred at room temperature overnight; monitored by LCMS; concentrated, a small amount of ether was added to slurry for 30 min, and filtered to obtain 5.29 g of white solid compound V with a purity of 99.94% and a yield of 91.83%. 1 H-NMR (400MHz, DMSO-d6) δ9.35 (s, 3H), 2.39 (s, 6H). 1 H-NMR spectrum is shown in Figure 1 , ELSD spectrum see Figure 2 .

[0075] Total yield of four steps: 42.78%.

[0076] Embodiment 2-7:

[0077] In order to optimize the preparation efficiency of the target product, Examples 2-7 explored the effects of the reaction conditions in step 1 on the product yield, and the reaction results are shown in Table 1; wherein, except for the different reaction conditions of step 1 shown in Table 1, the reaction conditions and operations of the other synthesis steps of Examples 2-7 are consistent with those in Example 1.

[0078] Table 1: Effects of different reaction conditions on step 1

[0079] Example catalyst Alkali Solvents light source Step 1 Yield 1 <![CDATA[CeCl 3 ]]> Sodium tert-butoxide <![CDATA[CH 3 CN+H 2 The]]> 440nm 67.23％ 2 <![CDATA[CeBr 3 ]]> Sodium tert-butoxide <![CDATA[CH 3 CN+H 2 The]]> 440nm 52.33％ 3 <![CDATA[Ce(SO 4 ) 2 ]]> Sodium Methanol <![CDATA[CH 3 CN+H 2 The]]> 365nm 13％ 4 <![CDATA[FeBr 2 ]]> Sodium tert-butoxide <![CDATA[CH 3 CN+H 2 The]]> 440nm 38％ 5 <![CDATA[CeCl 3 ]]> Sodium tert-butoxide <![CDATA[CH 2 Cl 2 ]]> 440nm 42％ 6 <![CDATA[FeBr 2 ]]> Sodium tert-butoxide <![CDATA[CH 3 RED 3 ]]> 440nm Trace 7 <![CDATA[CeCl 3 ]]> Potassium carbonate <![CDATA[CH 3 CN]]> 440nm 52％

[0080] Comparing Examples 1 and 2, it can be seen that under the same base, solvent and light source, Example 2 uses a different cerium catalyst and the reaction yield is reduced.

[0081] Comparing Examples 1 and 3, it can be seen that Example 3 uses different cerium catalysts, different bases and light sources with different wavelengths, and the reaction yield is significantly reduced.

[0082] Comparing Examples 1 and 4, it can be seen that under the same base, solvent and light source, when iron catalyst is used in Example 4, the reaction yield decreases.

[0083] Comparing Examples 1 and 5, it can be seen that in Example 5, under the same base, cerium catalyst and light source, different solvents are used, and the reaction yield decreases.

[0084] Comparing Examples 1 and 6, it can be seen that Example 6 uses an iron catalyst and acetone as a solvent, and almost no product is obtained.

[0085] Comparing Examples 1 and 7, it can be seen that the yield is reduced when the base is replaced in Example 7.

[0086] Embodiment 8:

[0087] In order to optimize the preparation efficiency of the target product, Example 8 explores the effect of the reaction conditions in step 2 on the product yield, and the reaction results are shown in Table 2; wherein, except for the different reaction conditions of step 2 shown in Table 2, the reaction conditions and operations of the other synthesis steps in Example 8 are consistent with those in Example 1.

[0088] Table 2: Effects of different reaction conditions on step 2

[0089]

[0090] Comparing Examples 1 and 8, it can be seen that the yield of Example 8 is significantly reduced when hydrolyzed at room temperature under alkaline conditions.

[0091] Embodiment 9-11:

[0092] In order to optimize the preparation efficiency of the target product, Examples 9-11 explored the effects of the reaction conditions in step 3 on the product yield, and the reaction results are shown in Table 3; wherein, except for the different reaction conditions of step 3 shown in Table 3, the reaction conditions and operations of the other synthesis steps of Examples 9-11 are consistent with those in Example 1.

[0093] Table 3: Effects of different reaction conditions on step 3

[0094]

[0095] Comparison of Examples 1 and 9 shows that when DPPA is increased to 1.5 equivalents in Example 9, the yield decreases;

[0096] Comparing Examples 1 and 10, it can be seen that when the base in Example 10 is replaced with N,N-diisopropylethylamine, the yield is significantly reduced;

[0097] Comparing Examples 1 and 11, it can be seen that Example 11 uses a mixed solvent and the yield remains substantially unchanged.

[0098] Embodiment 12:

[0099] Step 1: Preparation of Compound II

[0100] In an air atmosphere, compound Ⅰ (300 g, 1763 mmol, 1 equiv), acetonitrile (8815 mL) and water (8815 mL), trichloroisocyanuric acid (204.869 g, 881.503 mmol, 0.5 equiv), sodium tert-butoxide (50.83 g, 528.905 mmol, 0.3 equiv), and cerium chloride (43.453 g, 176.301 mmol, 0.1 equiv) were added to a 20 L jacketed reaction bottle; the temperature was controlled at 25 ° C, the reaction was allowed to react overnight with 440 nm light, and the reaction was monitored by GCMS to be complete. The reaction solution was diluted with petroleum ether (8800 mL), adjusted to pH = 3 with 6M hydrochloric acid, separated, and the aqueous phase was extracted with petroleum ether (3*2L). The organic phases were combined and washed once with 2M hydrochloric acid (2L), dried over anhydrous sodium sulfate, and concentrated to obtain 165 g of yellow solid compound II with a purity of >99% and a yield of 58.28%.

[0101] Step 2: Preparation of Compound III

[0102] Under nitrogen protection, compound II (165 g, 1027.397 mmol, 1 equiv), THF (2000 mL), and H 2 O (2000mL), heat to 50°C, slowly add concentrated sulfuric acid (514.74mL); control the temperature at 50°C to react overnight; monitor with GCMS. Cool to room temperature, concentrate most of the organic solvent, add water (2000mL), extract with dichloromethane (2*2000mL), collect the organic phase, dry and concentrate to obtain 148g of yellow solid compound III, with a purity of 87.3% and a yield of 98.28%.

[0103] Step 3: Preparation of Compound IV

[0104] Under nitrogen protection, compound III (148 g, 1009.756 mmol, 1 equiv), tert-butanol (4440 mL), TEA (306.54 g, 3029.268 mmol, 3 equiv) were added to a 5 L jacketed reaction bottle, and DPPA (305.68 g, 1110.732 mmol, 1.1 equiv) was slowly added dropwise at room temperature; after stirring at room temperature for 2 h, the temperature was raised to 90 ° C and refluxed overnight. The reaction was monitored to be complete by LCMS. The mixture was filtered, concentrated, diluted with water (2000 mL), extracted with ether (2×2000 mL), the organic phase was collected, washed with saturated sodium chloride solution (2000 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (chromatographic column packing: 100-200 mesh silica; wet loading after dissolving in a small amount of petroleum ether, eluent: petroleum ether) to obtain 204.7 g of white solid compound IV with a purity of >95% and a yield of 93.12%.

[0105] Step 4: Preparation of Compound V

[0106] Compound IV (204.7 g, 940.328 mmol, 1 equiv) was dissolved in 1,4-dioxane (1032 mL), and a 4M 1,4-dioxane solution of hydrogen chloride (1644 mL, 7 equiv) was slowly added dropwise under an ice bath, and stirred at room temperature overnight; LCMS monitoring; concentrated, a small amount of ether was added to slurry for 30 min, and filtered to obtain 114 g of white solid compound V with a purity of 98.3% and a yield of 77.37%. This batch of compound V 1 H-NMR spectrum is shown in Figure 3 , ELSD spectrum see Figure 4 .

[0107] Total yield of four steps: 41.27%.

[0108] Example 12 has been verified by 100-gram preparation under the reaction conditions of Example 1 and is suitable for industrial production.

Claims

1. A method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II, characterized in that: The method comprises the following steps: compound I, trichloroisocyanuric acid, a metal catalyst and a base are mixed in a solvent, and reacted under visible light illumination to obtain a 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II; 2. The method according to claim 1, characterized in that The metal catalyst is selected from a cerium catalyst and an iron catalyst; The base is selected from an organic base or an inorganic base; The solvent is selected from an organic solvent, water or a mixture of the two; The wavelength of the visible light is 400nm to 500nm; The reaction time is 6 to 20 hours, and the temperature is 5 to 35°C; The molar ratio of the compound I, trichloroisocyanuric acid, metal catalyst and base is 1: (0.3-0.7): (0.05-0.3): (0.1-0.5); The mass volume ratio of the compound I to the solvent is 1: (40-80) g / mL.

3. The method according to claim 2, characterized in that The cerium catalyst is selected from CeCl3, CeBr3, Ce(SO4)2; the iron catalyst is FeBr2; The organic base is sodium alkoxide, preferably sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium tert-butoxide, sodium n-butoxide or sodium isobutoxide; The inorganic base is potassium carbonate or sodium carbonate; The solvent is selected from an organic solvent and a mixture of an organic solvent and water, and the organic solvent is selected from acetonitrile and dichloromethane; in the mixture of the organic solvent and water, the volume ratio of the organic solvent to water is preferably 1:(0.5-2), more preferably 1:1; The wavelength of the visible light is 440nm; The reaction time is 8 to 14 hours, and the temperature is 10 to 30° C., preferably 25° C.; The molar ratio of the compound I, trichloroisocyanuric acid, metal catalyst and base is 1:0.5:0.1:0.3; The mass volume ratio of the compound I to the solvent is 1:59 g / mL.

4. A method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, characterized in that: The method comprises the following steps: (1) synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II according to the method described in any one of claims 1 to 3; (2) hydrolyzing the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II to obtain the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III; 5. The method according to claim 4, characterized in that In step (2), the hydrolysis is carried out under acidic conditions.

6. The method according to claim 5, characterized in that In step (2), the hydrolysis is carried out in the presence of concentrated sulfuric acid, the mass volume ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate II to the concentrated sulfuric acid is 1:(2-4), preferably 1:3; the hydrolysis temperature is 40-60°C, preferably 50°C; the hydrolysis is carried out in a mixture of tetrahydrofuran and water; the hydrolysis is carried out under the protection of an inert gas.

7. A method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate IV, characterized in that: The method comprises the following steps: (a) synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III according to the method described in any one of claims 4 to 6; (b) reacting 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide and a base in a solvent containing tert-butyl alcohol to obtain compound IV; 8. The method according to claim 7, characterized in that In step (b), the base is an inorganic base or an organic base, and the organic base is preferably triethylamine or N,N-diisopropylethylamine; the solvent is tert-butyl alcohol or a mixture of tert-butyl alcohol and toluene; step (b) comprises the following operations: (b1) 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide, base and solvent are mixed and reacted, concentrated, dissolved in dichloromethane, washed with water, and dried; (b2) solvent is added to dissolve, reacted, and compound IV is obtained; Preferably, in step (b1), the molar ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III, diphenylphosphoryl azide and the base is 1:(1.05-1.5):(2-4), preferably 1:1.1:3; the mass volume ratio of the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III to the solvent in step (b1) is 1:(5-30) g / mL, preferably 1:(10-20) g / mL; the 3-chlorobicyclo[1.1.1]pentylamine salt intermediate III is 1:(5-30) g / mL, preferably 1:(10-20) g / mL; The mass volume ratio of body III to the solvent in step (b2) is 1: (5-30) g / mL, preferably 1: (10-20) g / mL; the temperature of the reaction in step (b1) is 25±10°C, preferably 25±5°C, and the reaction time is 1-3 hours, preferably 2 hours; the temperature of the reaction in step (b2) is 80-110°C, preferably 90°C, and the reaction time is 6-20 hours, preferably 8-14 hours; the reaction is carried out under the protection of an inert gas.

9. A method for synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt, characterized in that: The method comprises the following steps: (i) synthesizing 3-chlorobicyclo[1.1.1]pentylamine salt intermediate IV according to the method described in any one of claims 7 to 8; (ii) Compound IV reacts with an acid to obtain 3-chlorobicyclo[1.1.1]pentylamine salt, i.e., Compound A; Wherein, X is an acid.

10. The method according to claim 9, characterized in that In step (ii), the acid is HCl.

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